Human stem cells efficiently colonize the bone marrow of lightly irradiated NOD/SCID mice and active produce cells in the B lymphocyte lineage pathway. With retroviral gene introduction methods, this system makes it possible to investigate many molecular aspects of human lymphocyte formation. Studies with mice indicate that B and T transcriptional repressor Id-1 and related molecules can block both pathways of differentiation at very early stages. While extracellular cues that regulate HLH function are poorly defined. Notch plays a role in fate decisions made by early lymphocyte precursors and may do so in part by blocking HLH protein products of the E2A gene. We will obtain detailed information about the normal patterns of gene expression for various HLH family members, Id proteins, Notch and Notch ligands in human B cell precursors. Experiments will then be done with the NOD/SCID chimera model to test cassettes into human stem cells before transplantation to NOD/SCID mice. Alterations in lymphocyte survival, proliferation and differentiation will be thoroughly characterized. It is also possible that malignancies will develop since E2A and related molecules are known to function as tumor suppressors. These experiments will provide information about mechanisms for normal regulation of the very earliest stage in human lymphopoiesis. The findings should be relevant to understanding immunodeficiency and autoimmune disease as well as malignancies.